Many genome-wide association studies have been unable to identify the genetic basis of traits that we know to be heritable. In some cases this is clearly due to an extraordinary degree of genetic complexity and epistasis. Yet in other cases the reasons are elusive. During their lifetimes, individuals commonly experience transient changes in gene expression as a result of different environmental stimuli. These responses are classically thought to have no heritable influence once they decay. However, we have recently discovered that such environmental stimuli frequently induce self-perpetuating changes in protein conformations. This occurs most commonly in proteins that regulate gene expression: transcription factors and RNA binding proteins. These self-templating changes in protein conformation can be broadly defined as `prions,' although their structures do not usually match the cross-beta sheet amyloids of the archetypical prion PrP. However, like known prions, corresponding changes in protein function are heritable from one generation to the next without any change to the genome2-4. In this sense, such protein-based inheritance represents and extreme form of epigenetics. The goals of this project are to systematically identify and characterize similar epigenetic elements in eukaryotic proteomes and investigate their influence on disease, development, and evolution. Our results will also providing a mechanistic understanding of how protein homeostasis fuels inheritance that is quasi-Lamarckian in character, but firmly rooted in a Darwinian framework of mutation and natural selection. New innovator funding will enable my laboratory to carry out the high-risk science necessary both to uncover the principles of this new realm of biology and to investigate the therapeutic implications of our findings.